Boromycin as a coccidiostat

ABSTRACT

Boromycin and its salts are active anticoccidial agents. They are included in compositions useful for the prevention and treatment of coccidiosis in poultry.

United States Patent Miller et al.

Feb. 4, 1975 BOROMYCIN AS A COCCIDIOSTAT Inventors: Brinton M. Miller, Middletown;

Richard W. Burg, Murray Hill, both of NJ.

Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: Feb. 28, 1974 Appl. No.: 446,875

U.S. Cl. 424/185 Int. Cl. A6lk 21/00, A6lk 27/00 Field of Search 424/185 References Cited OTHER PUBLICATIONS Pache et al., Chem. Abst., Vol. 71 (1969), page Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Francis H. Deef; J. Jerome Behan; Edmunde D. Riedi [57] ABSTRACT Boromycin and its salts are active anticoccidial agents. They are included in compositions useful for the prevention and treatment of coccidiosis in poultry.

3 Claims, N0 Drawings 1 BOROMYCIN AS A COCCIDIOSTAT SUMMARY OF THE INVENTION This invention relates generally to the usefulness of boromycin for the treatment and prevention of coccidiosis in susceptible animals especially in fowl, and particularly in poultry. ln addition, this invention relates to compositions including said boromycin as the active ingredient. intimately admixed with an inert carrier for administration to animals infected with coccidia. It is. therefore, an object of this invention to provide a method of treatment for coccidiosis using boromycin. It is also an object of this invention to include boromycin in compositions for administration to poultry which compositions are employed to treat coccidiosis. As used herein, the term treat includes administration to animals which have developed active symptoms of coccidiosis, as well as animals without overt symptoms, but that have been exposed to causative organisms. Further objects will become apparent upon a further reading of the description.

Coccidiosis is a common and widespread animal disease caused by several species of protozoan parasites of the genus Eimeria. ln chickens, implicated species include E. tenella, E. necalrix, E. uc'ervulina, E. HIllXiHlll, E. lzugam', and E. brunerli. E. tenella is the causative agent of a severe and often fatal infection of the caeca, which is manifested by severe and extensive hemorrhage, accumulation of blood in the caeca, and the passage of blood in the droppings. E. acervulina attacks the small intestine of the chick causing what is known as intestinal coccidiosis. Related species of coccidia such as E. meleagridis and E. adenoides are causative organisms of coccidiosis in turkeys. When left untreated, the severe forms of coccidiosis lead to poor weight gain, reduced feed efficiency and mortality in fowl. The elimination or control of this disease is, therefore, of paramount importance to the poultry raising industry.

Boromycin is an ionophoric macrolide and methods for obtaining it are disclosed in South African Pat. No.

LII

feed, although it may also be given dissolved or suspended in the drinking water. According to a preferred aspect of the invention, novel compositions for the treatment of coccidiosis are provided which comprise boromycin or a salt thereof intimately dispersed in or intimately admixed with an inert carrier or diluent.

The compositions which are a preferred feature of this invention are the so-called feed premixes in which a boromycin compound. i.c.. boromycin or a salt thereof is present in relatively large amounts and which are suitable for addition to the poultry feed either directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable for such compositions are animal feed ingredients such as distillers dried grains, corn meal. citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits. crushed limestone and the like. The boromycin compound is intimately dispersed or admixed throughout the solid inert carrier by methods such as grinding, stirring, milling, or tumbling. By selecting proper diluents and by altering the ratio of carrier to active ingredient, compositions of any desired concentration may be prepared. Formulations containing from about I to about by weight and preferably from about 245% by weight, of a boromycin compound are particularly suitable for addition to poultry feedstuffs. Those having from about 5-2071 by weight of coccidiostat are very satisfactory. The active compound is usually dispersed or mixed uniformly in the diluent but in some instances may be sorbed on 66/5860 issued June 3, 1967. There are included in this invention those salts of boromycin which can be formed by neutralizing the boromycin with a weak base such as sodium bicarbonate or potassium bicarbonate or other such weak bases having a monovalent anion to form the sodium, potassium or like salt, and which are physiologically acceptable.

Boromycin and its salts as hereinabove described, when used as anticoccidial agents are administered orally as a component of the animal feedstuff in the drinking water, in salt blocks, and in unit dosage forms I such as tablets, boluses, or drenches; or parenterally either in solution or in suspension in an aqueous medium. The vehicle in which the boromycin anticoccidial agent is distributed is an inert edible carrier or diluent. By an inert edible carrier or diluent is meant one that is nonreactive-with respect to the boromycin compound and that may be administered with safety to the animals to be treated. The carrier or diluent is preferably one that is or may be an ingredient of the animal feed.

Thus, the preferred embodiment of this invention are the compositions containing the above boromycin compounds which may be successfully employed to treat coccidiosis when administered to animals susceptible to coccidiosis preferably as a component of their the carrier. Since it is convenient for the feed manufacturer to use about one pound of feed supplement for each ton of finished feed, the preferred concentration in the supplement is usually a function of the level of active ingredient desired in the finished feed.

For treating poultry, the feed supplement is uniformly dispersed in the animal feed by suitable mixing or blending procedures.

Usually the feed supplements are further diluted with materials such as corn meal or soybean meal before being incorporated in the animal feed. In this intermediate processing step, the level of the boromycin compound in the carrier is brought down to about 0.1 to 1.0% by weight. This dilution serves to facilitate uniform distribution of the coccidiostat in the finished feed. The finished feed is one that contains a source of fat, protein, carbohydrate, minerals. vitamins, and other nutritional factors.

Very low levels of a boromycin compound in an animal feed are sufficient to afford good protection against coccidiosis in a susceptible animal. Preferably, the compound is administered in an amount equal to about 0.003 to 0.025% by weight of the feed. Optimum results are obtained by feeding at a level of about 0.006

' to 0.0125% by weight of the finished feed. For theraamount of boromycin activity can be obtained by employing less pure material derived from various stages of a boromycin fermentation including whole culture, filtered beer or mycelia. For example, the filtered beer Animal feed premixes having the following compositions are prepared by intimately mixing the boromycin compound and the particular edible solid diluent or diluents:

can without further purification be spray dried directly 5 into the inert carrier. When employing such a source of I boromycin activity, the material used must be assayed A Boromycin j' and the quantity employed be factored so it is equivapistme'rsdried grain, 5:5 lent to the above referred to concentrations. Boromycin I h b f l0 Soy-a mlllfee d 45.0 n e a ove iscussion o is imcn ion, emp asis Fm My, 400 has been placed on solid compositions wherein the ac- B rprny in .2." tive ingedient is mixed with an edible carrier in a feed D g g ssfiz a supplement, in a so-called premix or in the final feed- Com distillersgrgiins 55.0 stuff. This is the preferred method of administering the germ mm] boromycin or its salt. An alternate method oftreatment is to dissolve or suspend the boromycin compound in PP prem xes arc made by methe drinking water ofthe animals. The quantity of borochflmcal m f Q mlxmg of h Ingredients to mycin anticoccidial agent which may be administered umform dlstrlbuuor} of the actlve Compound and are in this fashion is, of course, limited by the solubility of added m l F an amount h the the product in Water or by the quantity that may be tratlon of boromycin or its salt is as herembefore specipended in the water without undue settling. Emulsifiers fled or surface active agents may be employed for this latter The foll9wlng cxfmples presented m order to purpose lustrate this invention and should not be construed as This invention is not limited to anticoccidial compo- 'm' of the mvemlon' sitions having boromycin type compounds as the sole active ingredient. Also contemplated within its scope is EXAMPLE I what might be called combined treatment" where a E n rv lina chicken assay boromycin compound'and one or more other anticoc- Th 1 Lday-QId f le white l ghorns, weighing cidials are administered concurrently. For such purb t n 75 t 90 each are maintained on a vitamin p COmPOSIIIOHS m y be p p Conilllnmg 11 supplemented diet (Pennfield I90) containing the samboromycin compound admixed with one or more other ple to be tested. One day later, each chicken is orally coccidiostats such as sulfaquinoxaline, other sulfa cominoculated with 4 X 10 sporulated oocysts of E. accrpounds, 4,4'-dinitrocarbanilide-2-hydroxy-4,6- vulina and maintained on the same diet for five more dimethylpyrimidine complex, .3-dinitr0diphenyldidays. Weights of each ofthe birds are recorded on days sulfide, 5-nitrofurfural semicarbazone, amprolium. l, 3,5, 6 and 7 during the assay; the rate of weight gains zoalene, buquinolate, ethopabate and the like. during days 1 to 5 (8,) is a parameter of drug toxicity, It will likewise be understood by those skilled in this whereas growth rate from day 5 to day 7 (B reflected art that special feed supplement formulations and finthe E. acervulina infection. The internal duodenal leished animal feeds containing vitamins, antibiotics, sions of each chicken are also examined. growth-promoting agents and other nutritional sub- The results are set forth below in Table I:

TABLE 1 Non- Medicated Boromycin Na Salt Normal infected in Feed Control Control 0.024 0.0 l 2 0.006

A. Response Active Active Moderately Active Lesion Score 0 0 1 Weight +39 +12 +3 B. Response Active Active Active Lesion Score 0 4 0 0 0 Weight +42 +22 1 l +29 +38 stances may include a boromycin compound of this in- EXAMPLE ll vention. A feed supplement of this type is the following:

E. tenella chicken ass-av Amount/lb. of

suprnememv Straight run white leghorn chicks, in groups of three gram-5 each, are weighed and placed in cages with wire floors. Riboflavin 0 64 They are fed, ad libirum, a standard laboratory ration ggcalcium pflmmhenme in which graded concentrations of test chemicals are Nlflclfl blended just prior to use. Nicarbazin and amprolium Choline chloride 50.00 vvitamin Bl2 Concentrate 130 mg are used as the reference standard. The normal and m- Procaine penicillin 0.84 fected birds are fed basal ration. On the second day of 31(lg0BtJJJQuJ/gg) the test, the chicks were each orally inoculated with Arsaniliczieid 13,36 50,000 sporulated oocysts of Eimeriu lane/la. Papers g t 'l g g tfig mluenc under cages are examined on 6th, 7th and 8th days of Boromycin 23:00 assay for presence or absence of bloody droppings. A

Distillers grains to 1 pound.

score of 0 is given if no bloody spots were observed.

TABLE ll Non- Medicated 7r Boromycin Nu Salt Normal Infected in Feed Control Control 0.024 ().()l 2 0.00h

A. Response Active Active Inactive Bloody Dropings Plus Lesion Score 23 0 1 l6.. Weight +28 +l9 l +l4 +Jl B. Response Active Active Inactive Bloody Dropings Plus Lesion Score 0 28 l 5 26 +28 +22 -l.5 +32 +22 Weight Number of bloody droppings per three birds are counted. On the 7th day of assay, the surviving birds are weighed, killed and examined for cecal coccidiosis lesions. Normal ceca are scored 0 and ccca with detectable, slight, moderate and maximal lesions are scored 1, 2, 3 and 4, respectively. When a bird dies and cecal coccidiosis lesions are present, a score of4 is recorded and the mortality noted.

A maximum infected bird has a score of 36 or more.- Fully active is assigned a score 0 to 6, and moderately active is assigned a score of 7 to 12. However, ifa coccidiosis mortality is noted and the other birds score 6 or more, the test compound is considered inactive.

The results are summarized in Table ll below:

What is claimed is:

2. A method according to claim 1 in which said compound is admixed with an inert carrier in the amount of 0.003 to 0.025% by weight.

3. A method according to claim 1 in which said compound is admixed with an inert carrier in the amount of from 0.006 to 0.0125% by weight. 

1. A METHOD FOR TREATING COEEIDIOSIS IN POULTRY WHICH COMPRISES ORALLY ADMINISTERING TO AN ANIMAL SUSCEPTIBLE TO COCCIDIOSIS AN ANTICOCCIDIALLY EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BOROMYCIN OR A SALT THEREOF.
 2. A method according to claim 1 in which said compound is admixed with an inert carrier in the amount of 0.003 to 0.025% by weight.
 3. A method according to claim 1 in which said compound is admixed with an inert carrier in the amount of from 0.006 to 0.0125% by weight. 